The amino acid L-glutamate is widely thought to act as a chemical transmitter substance at excitatory synapses within the central nervous system. Neuronal responses to glutamate are complex and appear to be mediated by at least three different receptor types, i.e., KA, QA and NMDA subtypes, each being named for their relatively specific ligands, i.e., kainic acid, quisqualic acid and N-methyl-D-aspartic acid, respectively.
NMDA receptors are strongly involved in nerve cell death which occurs following brain ischemia or hypoxia. Upon the occurrence of ischemic/hypoxic brain insults such as those which occur during spinal or head trauma, stroke or heart attack, an excessive release of endogenous glutamate occurs from nerve termiinals deprived of the energy supplies needed to retain the neurotransmitter. The excessive amounts of glutamate cause an over-stimulation of NMDA receptors on nearby neurons. Associated with the NMDA receptors is an ion channel. The recognition site, i.e., the NMDA receptor, is external to the ion channel. When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permitting a flow of cations across the cell membrane, e.g., Ca.sup.2+ and Na.sup.+ into the cell and K.sup.+ out of the cell. It is believed that this flux of ions, especially the influx of Ca.sup.2+ ions, caused by the interaction of glutamate with the NMDA receptor plays an important role in neuronal death. See, e.g., Rothman, S. M. and Olney, J. W., Trends in Neurosci. 10(7):299-302 (1987).
Agents which block responses to NMDA receptor activation therefore have potential therapeutic uses in the treatment of neurological disorders and nerve cell death resulting from hypoxia or hypoglycemia or following brain ischemia which occurs during stroke, trauma and heart attack. A number of disorders of the nervous system are associated with neurodegeneration that may be caused by over-activation of NMDA receptors. Antagonists of NMDA receptor-mediated responses have potential therefore for the treatment of such disorders as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and Down's Syndrome.
Research on the NMDA receptor-ion channel complex has led to the determination of a receptor site within the ion channel known as the PCP receptor. See Vincent, J. P., Kartalovski, B., Geneste, P., Kamenka, J. M. and Lazdunski, M., Proc. Natl. Acad. Sci. USA 76:4678-4682 (1979); Zukin, S. R. and Zukin, R. S., Proc. Nail. Acad. Sci. USA 76:5372-5376 (1979); Sonders, M. S., Keana, J. F. W. and Weber, E., Trends in Neurosci. 11(1):37-40 (1988); and Anis, N. A., Berry, S. C., Burton, N. R. and Lodge, D., Br. J. Pharmacol. 79:565-575 (1983). Compounds which bind to the PCP receptor can act as ion channel blockers, thereby interrupting the flow of ions across the cell membrane. In this manner, agents which interact with the PCP receptor act as non-competitive blockers, reducing the agonist action of glutamate at the NMDA receptor.
Known PCP receptor ligands include PCP [angel dust], i.e., phencyclidine, analogues such as 1-[1-(2-thienyl)-cyclohexyl]-piperidine (TCP), benzomorphan (sigma) opiates, dioxolanes and 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine (i.e., the drug MK-801, see U.S. Pat. No. 4,399,141). See, also, Wong, E. H. F., Kemp, J. A., Priestly, T., Knight, A. R., Woodruff, G. N., and Iversen, L. I., Proc. Natl. Acad. Sci. USA 83:7104-7108 (1986). MK-801 is apparently the most potent selective PCP receptor ligand/NMDA channel blocker known to date.
European Patent Application Publication No. 0230370, Published Jul. 29, 1987, discloses compounds having the Formula(I): ##STR1## Where R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are H, the compound is MK-801. This compound and derivatives thereof are the subject of a patent to Anderson et al., U.S. Pat. No. 4,399,141 (1983).
U.S. Pat. No. 4,374,838 to Anderson et al. (1983) discloses compounds related to MK-801 of the Formula (II): ##STR2## which are useful as muscle relaxants, antidepressants, anticonvulsants, and in the treatment of mixed anxiety-depression, minimal brain dysfunction, and extrapyramidal disorders.
U.S. Pat. No. 4,064,139 to Anderson et al. (1977) discloses compounds related to MK-801 of Formula (III): ##STR3## which are useful as minor tranquilizers, anticonvulsants, muscle relaxants, and in the treatment of extrapyramidal disorders such as Parkinson's disease.
U.S. Pat. No. 3,509,158 to Dobson et al. (1970) discloses 10,5-(iminomethano)-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene and derivatives thereof of the Formula (IV): ##STR4## wherein Z represents a group selected from the group consisting of ##STR5##
These compound are reportedly useful as trichomonacidal, anti-convulsant, anti-parasitic, anti-inflammatory and hypotensive agents.
U.S. Pat. No. 4,232,158 to Shepard et al. (1980), discloses 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines and derivatives thereof having the following structural Formula (V): ##STR6## These compounds are reported useful as anti-anxiety agents, as muscle relaxants and in the treatment of extrapyramidal disorders such as Parkinson's disease.
U.S. Pat. No. 3,641,038 to Davis et al. (1972), discloses 10,11-dihydro-10,5-(iminomethano)-5H-dibenzo[a,d]-cyclohepten-10-ol derivatives having the Formula (VI): ##STR7## These compounds reportedly possess anti-convulsant activities.
U.S. Pat. No. 3,542,787 to Dobson et al. (1970), discloses 10,11-dihydro-5,10-(iminomethano)-5H-dibenzo[a,d]-cycohepten-13-imine having the Formula (VII): ##STR8## This compound reportedly has hypotensive properties.
U.S. Pat. No. 3,597,433 to Dobson et al. (1971), discloses 10,11-dihydro-5,10-(iminomethano)-5H-dibenzo[a,d]-cycloheptene and its derivatives having the following Formula (VIII): ##STR9## These compounds reportedly have anticonvulsant activity substantially free from ataxic side-effects.
U.S. Pat. No. 3,716,541 to Dobson et al. (1973), discloses 11-substituted derivatives of 10,11-dihydro-5,10-(iminomethano)-5H-dibenzo[a,d]-cycloheptene having the Formula (IX): ##STR10## The compounds reportedly exhibit central nervous system depressant and anticonvulsant properties without causing ataxia.
U.S. Pat. No. 3,717,641 to Kocsis et al. (1973), discloses 5,6,11,12-tetrahydrodibenzo[a,e]cycloheptene-5,11-imine having the Formula (X): ##STR11## These compounds reportedly have anti-tussive and musculotropic spasmolytic activities.
U.S. Pat. No. 3,892,756 to Nedelec et al. (1975), discloses 5,10-imino-dibenzo-cycloheptenes having the Formula (XI): ##STR12## These compounds are reportedly useful as stimulants and anticonvulsants.
U.S. Pat. No. 4,009,273 to Nedelec el al. (1977), discloses compounds of the Formula (XII): ##STR13## These compounds are reportedly useful as stimulants and anticonvulsants.
U.S. Pat. No. 4,052,508 to Anderson et al. (1977), discloses dihydroanthracen imines and derivatives thereof having the Formula (XIII): ##STR14## These compounds are reportedly useful as minor tranquilizers, anticonvulsants, muscle relaxants, and in the treatment of extrapyramidal disorders such as Parkinson's disease.
U.S. Pat. No. 4,064,139 to Anderson et al. (1977), discloses substituted 9,10-dihydroanthlracene-9,10-imines having the Formula (XIV): ##STR15## These compounds are reportedly useful as minor tranquilizers, anticonvulsants, muscle relaxants, and in the treatment of extrapyramidal disorders such as Parkinson's disease.
Despite the development of the above-mentioned derivatives, a need continues to exist for new methods for the treatment or prevention of neuronal loss associated with stroke, ischemia, CNS trauma, and hypoglycemia, as well as for the treatment or prevention of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Down's syndrome.